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Abstract

Introduction

The ataxia-telangiectasia mutated (ATM) gene (MIM ID 208900) encodes a protein kinase that plays a significant role in the
activation of cellular responses to DNA double-strand breaks through subsequent phosphorylation
of central players in the DNA damage-response pathway. Recent studies have confirmed
that some specific variants in the ATM gene are associated with increased breast cancer (BC) risk. However, the magnitude
of risk and the subset of variants that are pathogenic for breast cancer remain unresolved.

Methods

To investigate the role of ATM in BC susceptibility, we studied 76 rare sequence variants in the ATM gene in a case-control family study of 2,570 cases of breast cancer and 1,448 controls.
The variants were grouped into three categories based on their likely pathogenicity,
as determined by in silico analysis and analyzed by conditional logistic regression. Likely pathogenic sequence
variants were genotyped in 129 family members of 27 carrier probands (15 of which
carried c.7271T > G), and modified segregation analysis was used to estimate the BC
penetrance associated with these rare ATM variants.

Results

In the case-control analysis, we observed an odds ratio of 2.55 and 95% confidence
interval (CI, 0.54 to 12.0) for the most likely deleterious variants. In the family-based
analyses, the maximum-likelihood estimate of the increased risk associated with these
variants was hazard ratio (HR) = 6.88 (95% CI, 2.33 to 20.3; P = 0.00008), corresponding to a 60% cumulative risk of BC by age 80 years. Analysis
of loss of heterozygosity (LOH) in 18 breast tumors from women carrying likely pathogenic
rare sequence variants revealed no consistent pattern of loss of the ATM variant.

Conclusions

The risk estimates from this study suggest that women carrying the pathogenic variant,
ATM c.7271T > G, or truncating mutations demonstrate a significantly increased risk of
breast cancer with a penetrance that appears similar to that conferred by germline
mutations in BRCA2.

Introduction

The ataxia-telangiectasia mutated (ATM) gene (MIM ID 208900) encodes a protein kinase that plays a major role in activating
cellular responses to DNA double-strand breaks through downstream phosphorylation
of central players in the DNA damage-response pathways, including BRCA1, p53, and
Chk2 [1].

More than 20 years ago, Swift et al. [2] reported that female relatives of patients with the autosomal recessive condition,
ataxia-telangiectasia (AT), have an elevated risk of cancer, particularly breast cancer.
Since the cloning of the ATM gene in 1995 [3], many case-control studies have carried out mutation screening and single nucleotide
polymorphism (SNP) genotyping to clarify the role of ATM genetic variation in breast cancer predisposition [4-10]. Initially, most mutation-screening studies were limited to protein-truncating mutations
identified by using the protein-truncating test [11], and many of them were underpowered [12].

The role of ATM variants in breast cancer predisposition remained controversial until Renwick et al. [13] screened a series of "familial" breast cancer cases selected for having a strong
family history and controls unselected for family history of breast cancer. Invoking
a multiplicative model in which risk modified a presumed underlying polygenic effect,
they estimated that the variants that are known to cause AT in the bi-allelic state
confer, on average, a moderately increased risk of breast cancer of about 2.4-fold
(95% confidence interval (CI), 1.51 to 3.78) (see also [14]). However, this study did not distinguish between the effects of protein-truncating
and missense mutations, although Gatti et al. [15] had hypothesised in 1999 that, compared with protein-truncating mutations, some missense
variants in ATM might act as dominant negatives and confer a particularly high risk of breast cancer
when heterozygous, although causing a milder form of AT when homozygous.

To determine which rare missense variants in ATM were likely to confer an increased risk of breast cancer, and to compare this with
the risk conferred by protein-truncating mutations, we previously carried out a meta-analysis
of published data and also mutation screened almost 1,000 breast cancer cases and
a similar number of controls [16]. In addition, that study classified the rare missense variants by using an in silico missense substitution analysis that provides a ranking of missense variants from evolutionarily
most likely (C0) to least likely (C65). We found marginal evidence that protein-truncating
(T) and splice-site junction (SJ) mutations confer on average a moderately increased
risk of breast cancer (odds ratio (OR), 2.3; 95% CI, 1.1 to 4.8), but stronger evidence
that a subset of rare, evolutionarily unlikely missense (rMS) C65 substitutions conferred
on average a higher risk of breast cancer (OR, 18; 95% CI, 3 to 120).

To define better the risks associated with these classes of ATM variants, and to determine whether they were likely to act as dominant negatives,
we genotyped a large panel of rare missense variants, as well as truncating and splice-junction
mutations, in breast cancer cases and controls from four large studies. We also genotyped
all available relatives of breast cancer cases found to carry putative breast-cancer
associated ATM variants to estimate their penetrance. In addition, we carried out loss of heterozygosity
(LOH) analyses and a review of the pathology of breast tumors from these mutation
carriers.

Materials and methods

Subjects

We studied Caucasian cases of breast cancer (n = 2,517 invasive and 53 DCIS) and controls (n = 1,448) from three sources: (a) population-based case and control breast cancer families
from the NCI-sponsored Breast Cancer Family Registry (BCFR) [17]; (b) a clinic-based resource of Australian and New Zealand multiple-case breast cancer
families from the Kathleen Cuningham Foundation Consortium for Research on Familial
Breast Cancer (kConFab) [18]; and (c) Australian female controls chosen from the Red Cross Blood Bank to be ethnically
and frequency matched for age to the age at diagnosis of kConFab cases [19] (Table 1). The kConFab cases were those from whom DNA was available who had the youngest age
at diagnosis in the family. All subjects in these studies provided informed consent
for participation in genetic and family studies. We excluded any subjects who had
previously been included in the sequencing study of Tavtigian [16] but noted that some of the included BCFR subjects overlap with those of Bernstein
et al. [10], although they genotyped only two variants, one of which is in our iPLEX [10]. The individual resource collections (BCFR, kConFab), as well as the specific ATM study, have been approved by the relevant ethical committees.

Selection of ATM variants and genotyping

Missense variants and in-frame deletions were assessed for the degree of conservation
within the ATM multiple protein sequence alignment and for the predicted severity
of the amino acid substitution, according to the Align-GVGD class, as previously described
[16,20]. We selected all the A-GVGD class C55/C65 variants reported previously [16], as well as a subset of the C0, C15, C25, C35, and C45 variants (Additional file
1). In addition, we included three variants identified in the literature [13,21] and 17 that we had found by sequencing of familial breast cancer cases from the population-based
(Northern California, Ontario, Australia) and clinic-based (Philadelphia, New York,
Utah) sites of the BCFR (unpublished data). The MassARRAY assay design software (Version
3.1) was used to select oligonucleotide sequences that were best suited for genotyping
according to the guidelines of Sequenom Inc San Diego, CA, USA. Sequences are available
on request. Primer extension reactions were carried out according to the manufacturer's
instructions for iPLEX chemistry. Genotypes were analyzed by using Sequenom TYPER
software (Version 3.1). Positive controls for 67 of the 79 variants were included
in the iPLEX genotyping. All the rare variants detected by iPLEX and a random selection
of the common variants (for QC purposes) were confirmed by direct sequencing by using
newly designed PCR primers. In addition, we applied similar QC criteria to those used
by the Breast Cancer Association Consortium [22]. Forty-five samples failed QC, but only three of 79 genotyped variants failed QC
(ATMc.6067G > A; ATMc.6820G > A; ATMc.8741T > C). We classified the 76 variants into
three groups: Group 1 consisted of 36 missense variants with an A-GVGD class of C0
or C15. Group 2 consisted of a total of 18 variants comprising intronic variants (other
than those at ± 1 or 2); variants in A-GVGD classes C25, C35, C45; as well as variants
in class C55 or C65 that fell outside the FAT and kinase domains of the ATM protein.
Group 3 consisted of 22 C55 and C65 variants in the FAT and kinase domains [16], as well as protein-truncating variants (either splice, nonsense, or frameshift).

Family genotyping and loss of heterozygosity analysis

To estimate the penetrance of the likely deleterious ATM variants, 129 family members of women who had been found to carry a truncating mutation
(n = 10), splice-site variant (n = 1), or evolutionarily unlikely missense substitution (C65 and C55) in the FAT, kinase,
and FATC domains (n = 16) were genotyped for the respective variant by direct sequencing (Table 2). In eight of these families, no additional DNA samples were available, but because
they were from population-based sources, they were informative for the penetrance
estimation. Twenty-four tumor blocks were available for LOH analysis from 18 different
affected cases and female relatives carrying a putative breast-cancer associated variant.
Sections were cut, and one slide was stained with hematoxylin and eosin (H&E) and
reviewed by a pathologist (LdS). If the section contained at least 70% tumor cells,
then the slide from an adjacent unstained section was macro-dissected and DNA isolated
[23]. For two cases in which fewer than 70% tumor cells were present in the section, tumor
cells were collected by laser capture micro-dissection (LCM) before DNA isolation
[24]. Primers that spanned the relevant region were then designed to generate a small
PCR product, and the tumor and germline DNA were sequenced in tandem. LOH was scored
by the absence of the heterozygous peak seen in the germline sample.

Table 2. Characteristics of the families used in the estimation of ATM penetrance

Pathology review

A blinded pathology review was performed by one of us (SRL) on 35 H&E slides of ATM-positive breast tumors (from 21 different carriers of Group 3 ATM variants) and H&E slides of 38 control breast tumors (age matched within 6 years)
ascertained from the Royal Brisbane and Women's Hospital between 2004 and 2009. The
slides were scored for pathologic features by using a modified pro forma that was
initially developed for studies on the pathology of BRCA-associated cancers. Specifically,
we assessed for the presence of in situ disease (LCIS and DCIS), invasive tumor type, and overall nuclear grade by using the
modified Nottingham Grading System [25], and for the presence of apocrine, "basal" (pushing margins, central acellular or
necrotic zones, lymphocytic infiltrates) and squamous differentiation. These features
were assessed without ancillary immunohistochemical methods.

Statistical methods

Conditional logistic regression was used to examine the associations between variants
in a given class and the risk of breast cancer, stratified by study center, by using
a case-control design. To guard against results driven by individual study centers,
we also performed Mantel-Haenszel χ2 analysis comparing each variant group against the reference, stratified by study center.
All analyses were performed by using STATA 10.0 (Statcorp, College Station, TX).

Penetrance of ATM variants was estimated by using modified segregation analysis of family genotypes
adjusted for ascertainment. Models were fitted under maximum likelihood theory by
using the statistical package Mendel///version 3.2 [26]. Noncarriers were assumed to be at population risks specific to Australia, Canada,
and the United States, with incidence rates taken from cancer registry data obtained
from Cancer Incidence in Five Continents, VIII (IARC, Lyon), and hazard ratios (HR,
the age-specific breast cancer incidence rate in carriers divided by the relevant
population rate) were estimated. Ascertainment was accounted for by conditioning the
likelihood of each family on the proband's genotype and phenotype (for population-based
families that were selected irrespective of family history) or on all phenotypes and
the proband's genotype (for clinic- and population-based families that had been selected
because of a family history).

As in Antoniou et al. [27,28], a mixed model [29] was used that incorporated the effect of an unmeasured polygenic factor on breast
cancer risk in addition to any effect due to the ATM variant segregating in the pedigree. P Values for the modified segregation analyses were based on the likelihood ratio test
and were two-sided. Cumulative risk estimates were calculated from the hazard-ratio
estimates as 1 minus the exponential of the cumulative incidence, and the corresponding
confidence intervals were calculated by using a parametric bootstrap with 5,000 replications.
The model assumed a dominant mode of action of the ATM variants on breast cancer risks and a combined allele frequency of 0.001 for the variants
in the population.

In separate analyses, we examined the risk associated with these ATM variants compared with those associated with BRCA2, as estimated by Antoniou et al., 2003 [30]. In these analyses, the age-specific HR (by decade) was assumed to be a constant
multiple of the Antoniou et al. estimate, with cumulative penetrances re-estimated at each trial value of the multiplier.
This allowed a similar pattern of age-specific effects as in BRCA2, but required estimation of only a single parameter.

Results

Of the 76 ATM variants that passed QC, 29 were observed one or more times in the analyzed set of
2,570 cases and 1,448 controls (Additional file 1). Table 3 shows the distribution of variants and number of cases and controls by group and
the results of the logistic regression. Overall, no significant association was found
between any variant group and the risk of breast cancer. In particular, we observed
an odds ratio of 2.55; 95% CI (0.54 to 12.0) for the Group 3 variants, which included
the most likely deleterious missense variants and the truncating variants. No evidence
was apparent for any heterogeneity in odds ratios between the four study centers.
Inclusion of age into the model did not change the results, nor did exclusion of 163
Ashkenazi Jewish women, who were overrepresented in cases and might have harbored
a founder mutation (results not shown). Similarly, exclusion of the 53 DCIS cases
had little effect on the results. In addition, to account for individual failed assays
(after eliminating those that had failed 16 or more assays), we estimated the probability
that a given individual belonged to each group based on the number of failed assays
composing that group.

Table 3. Breast cancer risk associated with each group of ATM variants

Penetrance analysis in families

We genotyped additional relatives in all 27 families in which putative pathogenic
variants had been identified. The specific variants included 16 missense variants,
of which 15 were p.Val2424Gly (c.7271T > G) (rs28904921), seven were frameshifts (of
which four were c.3802delG), three were nonsense mutations, and one was a consensus
splice-site variant (all variants included in the family analysis are indicated in
Table 2). In total, 129 additional DNA samples were available for genotyping in relatives
of the probands; 86 were negative for the family-specific variant (10 affected and
76 unaffected individuals), and 43 were positive (14 affected and 29 unaffected individuals).
In the analysis of the ATM family data by using a mixed model (ATM gene plus polygenic background), the presence of an ATM variant increased breast cancer risk by an estimated factor of 6.88 (95% CI, 2.33
to 20.3; P = 0.00008) and did not depend on age (P = 0.9). The estimated cumulative risks of developing breast cancer for female carriers,
assuming US SEER incidence rates, are shown in Figure 1. Separate analyses of the 15 families carrying the ATM c.7271T > G variant found that this variant increased breast cancer risk by a factor
of 8.0 (95% CI, 2.3 to 27.4; P = 0.0005) compared with 4.4 (95% CI, 0.70 to 28.1; P = 0.053) for families with other variants.

Under the assumption that the penetrance of the ATM variants was a constant multiplier of the BRCA2 penetrance, the value of the multiplier that resulted in the best fit to the pedigree
data was 0.75 (95% CI, 0.33 to 1.50), indicating that the ATM alleles segregating in these 27 families were associated with risks equivalent to
75% those of BRCA2. In the 16 families with a missense variant, the penetrance estimate was 1.1 that
of BRCA2, whereas in the 11 families with a truncating or splice junction (TSJ) mutation,
the best estimate was 0.3, although this difference was not significant (χ2 = 2.99; P = 0.08).

Loss of heterozygosity analysis

LOH results for the 18 different affected women are summarized in Table 4. Identical LOH results were obtained for all six cases in which two different blocks
from the same tumor were tested. Four of the seven cases with a truncating mutation
in ATM showed loss of the mutant allele, and the remainder showed no LOH. Of the eight cases
with the C65 variant, p.Val2424Gly (ATMc.7271T > G), one showed loss of the wild-type,
one showed partial loss of the mutant, and the remainder showed no LOH. Of the remaining
two cases with C55 or C65 variants, one showed loss of the mutant allele, and the
other had no LOH.

Pathology review

We compared the ATM-positive tumors with a set of age-matched control breast tumors.
No statistically significant difference was noted in overall histologic grade. Looking
at the three individual components of grade (tubule formation, nuclear pleomorphism,
and mitotic counts), no apparent differences were related to pleomorphism or tubule
scores. However, a marginally significant association was seen between the mitotic
score (exact P = 0.049), largely because of the paucity of ATM tumors with a mitotic score of 3 (two of 18 compared with 14 of 34 of the control
tumors). This was also supported by analysis of the quantitative count of mitoses
per 10 high-power fields, with some suggestion of lower mitotic rates in the ATM tumors than in the control tumors (7.9 versus 19.0 mitoses per 10 high-power fields;
P = 0.02 by t test, with Welch correction for unequal variances).

Discussion

Gatti et al. [15] hypothesised in 1999 that, compared with protein-truncating mutations, some missense
variants in ATM might act as dominant negatives and confer a particularly high risk of breast cancer
when heterozygous, while causing a milder form of AT, when homozygous. It was later
shown that a missense mutation, ATM c.7271T > G (p.Val2424Gly), appears to confer a high risk of breast cancer and to act
as a dominant negative [31,32]. This mutation was first identified in a Scottish family with a mild form of AT [33] and subsequently found in an Australian family [31], but initial estimates of the magnitude of risk were imprecise. Screening of nearly
4,000 population-based breast cancer cases for this mutation identified another six
carrier families, and, based on their breast cancer family histories, risk for this
mutation was estimated to be increased by ninefold (95% CI, 4 to 19) [10].

To refine the risks associated with different classes of ATM variants, and to examine the molecular pathologic characteristics of ATM-positive tumors, we genotyped 76 rare ATM variants in 2,570 breast cancer cases and 1,448 controls. In addition, we genotyped
specific variants in the relatives of probands carrying ATM variants judged likely to be pathogenic. Because, by definition, we expect variants
conferring moderate to high risks of breast cancer to be rare in the general population,
traditional case-control studies of even several thousand cases and controls are typically
underpowered to detect associations with these sequence variants. We could potentially
pool these variants and compare the aggregate frequency of these variants to increase
power. However, the power is often reduced because of the inherent heterogeneity of
such variants, in which only a minority is associated with increased risk. One strategy
to address this problem is to use in silico methods to group variants into categories based on their probability of representing
variants that are damaging to the normal protein function. Although a number of such
methods are available, we used the Align-GVGD that has been applied to a number of
genes, including BRCA1, BRCA2, CHEK2, ATM, and mismatch-repair genes [20,34]. However, even with this stratification, we still had insufficient power to detect
an association with breast cancer with even the most likely pathogenic variants (OR,
2.55 (95% CI, 0.54 to 12.0), although the effect sizes were comparable with those
previously reported [16].

As in other studies of ATM and breast cancer risk [13,16], the most common pathogenic variant in our study was the ATM c.7271T > G (p.Val2424Gly). Renwick et al. [13] did not compare the breast cancer risks associated with protein-truncating versus
missense mutations in ATM. Bernstein et al. [10] had previously identified seven carriers of this mutation in the three population-based
sites of the BCFR; however, no family members were genotyped in this study. In our
study of these same case-control studies, we independently identified the same four
mutation carriers from the Ontario BCFR site, as well as the one carrier from the
Australian BCFR site. We did not identify the two ATM c.7271T > G (p.Val2424Gly) mutation carriers from the Northern California BCFR site
that Bernstein et al. [10] had identified because one was subsequently found also to carry a pathogenic BRCA2 mutation (and was thus excluded from our study), and for the other, no DNA sample
was available for our analyses. This missense ATM variant was first reported to be associated with a mild form of AT and might have
originated in the Orkney Islands in Scotland and then spread throughout populations
with large numbers of Scottish immigrant populations, such as those of Australia.
Our analysis of independent samples from four case-control studies provided some support
of the observation by Tavtigian et al. [31,32] that this mutation (and perhaps other similar missense mutations with dominant-negative
activity) confers a higher risk of breast cancer than do protein-truncating mutations.

As a second approach to verifying and characterizing the role of ATM sequence variants in breast cancer, we took advantage of the fact that the resources
from which the cases were drawn had also included the relatives of those cases, providing
us with the ability to genotype both affected and unaffected relatives of cases in
which potentially pathogenic variants had been identified. As in Bernstein et al. [10], even in cases in which no additional samples were available, the fact that the some
of the breast cancer cases analyzed were from the population-based sites of the BCFR
allowed us to make inferences based on the observed incidence of cancer in relatives
of index cases carrying the specific ATM variant. Our analyses of family data in 27 families of carriers of either protein-truncating
(n = 11) or rare, evolutionarily unlikely, potentially damaging missense mutations (n = 16) demonstrated a significantly increased risk of breast cancer with a penetrance
that appears similar to that conferred by germline mutations in BRCA2. However, even in a study of this size, the confidence intervals are wide. Suggestive
evidence also was noted from the family-based analysis that a higher risk was associated
with the ATM c.7271T > G (p.Val2424Gly) mutation than with truncating mutations, although these
differences were not statistically significant because of the relatively small sample
size of families. The penetrance associated with truncating mutations was only marginally
significant. If our estimates of breast cancer risk are correct, then women carrying
the ATM c.7271T > G variant would be at sufficiently high risk to warrant screening for at
least this variant in multiple-case families without mutations in BRCA1 or BRCA2. If such a variant is identified, these women could be counseled in a manner similar
to that with BRCA2 carriers, and those affected with breast cancer might also be candidates for treatment
with PARP inhibitors in a manner similar to that with BRCA1 and BRCA2 carriers. This suggestion is based on the evidence that the inhibition of PARP1 is
synthetically lethal with mutation or loss of ATM, and the effect is mediated through
mitotic catastrophe independent of apoptosis [35,36].

Consistent with the dominant-negative hypothesis [15,31,32], we did not observe consistent loss of the wild-type allele in tumors from carriers
of missense variants. Loss of both the wild-type and the variant allele was observed
in different tumors, whereas some tumors from missense carriers exhibited no loss
of either allele. Interestingly, we noted that all four carriers of truncating mutations,
in which LOH was present, showed loss of the variant, rather than of the wild type,
as would be expected for a tumor-suppressor gene. This apparent bias in allelic loss
requires further investigation in larger studies.

Blinded pathology review of 35 tumors from cases who carried a likely deleterious
ATM variant and a hospital-based series of 38 age-matched control breast tumors did not
reveal any distinctive pattern of histopathologic characteristics, as had been previously
reported in BRCA1 tumors [37]. However, some evidence suggested that ATM tumors were associated with a lower mitotic index than were control tumors, which
is in contrast to the clear increase in mitotic index associated with BRCA1 tumors [37]. In agreement with this, our previous expression analysis of six tumors from ATM c.7271T > G mutation carriers showed that they were all luminal A or B tumors, and
we would not have expected them to share histopathologic characteristics with BRCA1 tumors [32]. In contrast to the evidence of Dork et al. [12], who reported an increased frequency of lobular breast cancers in ATM carriers, we did not observe this in our series, with half the lobular or mixed lobular/ductal
in each group (P = 0.66).

Conclusions

This is the largest study to date investigating large numbers of rare missense variants
in the ATM gene for association with breast cancer risk. In addition to the standard case-control
approach, we used the power of a family-based design inherent in the two resources
from which the cases and controls were derived (BCFR and kConFab) to estimate more
precisely the risks of breast cancer through genotyping of relatives of the probands
carrying the putative pathogenic variants. Although Bernstein et al. [10] used a similar approach and five probands overlapped between the two studies; it
should be noted that, unlike our study, Bernstein et al. did not include genotypes of additional relatives from these families in their analysis.
Taken as a whole, our study adds to the growing body of evidence that a subset of
rare ATM variants confers levels of risk that may have clinical implications for the women
who carry them, as well as for their at-risk family members.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

GCT participated in the writing of the manuscript, conceived and designed the study,
and directed the laboratory work. DEG and JLH participated in the writing of the manuscript
and performed the statistical analyses. SH participated in the writing of the manuscript
and performed the iPLEX genotyping and the LOH studies. MCS and EMJ participated in
the writing of the manuscript and managed the data. PJO participated in the writing
of the manuscript and performed the DNA sequencing. KKK participated in the writing
of the manuscript. XC performed the iPLEX genotyping and the LOH studies. JGD performed
the statistical analyses. MJD, SB, ABS, IA, and MBT managed the data. SL and LdS performed
the pathology review. All authors read and approved the final manuscript.

Acknowledgements

This work was supported by National Institutes of Health (NIH) grant RO1-CA100352
and R01-CA121245. KKK and GCT are Senior Principal Research Fellows of the NHMRC.
The Breast Cancer Family Registry (BCFR) is supported by the National Cancer Institute,
National Institutes of Health under RFA-CA-06-503 and through cooperative agreements
with members of the BCFR and Principal Investigators, including Cancer Care Ontario
(U01 CA69467), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631),
Huntsman Cancer Institute (U01 CA69446), Northern California Cancer Center (U01 CA69417),
University of Melbourne (U01 CA69638), and the Georgetown University Informatics Support
Center (RFP No. N02PC45022-46). Samples from the NCCC, FCCC, and HCI were processed
and distributed by the Coriell Institute for Medical Research. The content of this
article does not necessarily reflect the views or policies of the National Cancer
Institute or any of the collaborating centers in the BCFR, nor does mention of trade
names, commercial products, or organizations imply endorsement by the U.S. Government
or the BCFR. We thank Heather Thorne, Eveline Niedermayr, all the kConFab research
nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical
Follow Up Study (funded 2001-2009 by NHMRC and currently by the National Breast Cancer
Foundation and Cancer Australia 628333) for their contributions to this resource,
and the many families who contribute to kConFab. kConFab is supported by grants from
the National Breast Cancer Foundation, the National Health and Medical Research Council
(NHMRC), and by the Queensland Cancer Fund, the Cancer Councils of New South Wales,
Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia.